Regulation of chromaffin cell secretion and protein kinase C activity by chronic phorbol ester treatment.
Bovine adrenal chromaffin cells were exposed to phorbol esters to determine the effects of reduced levels of protein kinase C on secretion of hormones. Treatment with active phorbol esters such as 4 beta-phorbol 12, 13-didecanoate (PDD) reduced levels of protein kinase C activity with a maximal 80-90% reduction in activity after 16-24 h treatment (greater than or equal to 500 nM PDD). Treatment with PDD also inhibited catecholamine secretion from chromaffin cells evoked by nicotine, barium, and scorpion venom (50-70%, t1/2 approximately 6 h) and by veratridine (80%, t1/2 less than 15 min). Secretion induced by these agents in phorbol ester-treated cells returned to that of untreated cells by 3-4 days despite no recovery of protein kinase C activity. Potassium-evoked secretion was not inhibited by phorbol ester treatment. Catecholamine secretion from digitonin-permeabilized cells was more sensitive to calcium between 1 and 24 h, but not greater than or equal to 48 h, after addition of phorbol ester. The results suggest that phorbol esters inhibit secretion by activation of protein kinase C resulting in inhibition of ion channels or receptors but not of the secretory machinery itself; hence, protein kinase C may usually machinery itself; hence, protein kinase C may usually attenuate secretory responses in the adrenal chromaffin cell.
Wilson
S P
SP
Department of Pharmacology, School of Medicine, University of South Carolina, Columbia 29208.
D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002838:Chromaffin System / Q000378:metabolism*; D015536:Down-Regulation; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*
D002395:Catecholamines; D010703:Phorbol Esters; C008876:phorbol-12,13-didecanoate; D009538:Nicotine; D011493:Protein Kinase C